1. Field of the Invention
This invention relates to macrolactams having anti-tumor properties and methods for their preparation and use.
2. Description of Related Art
Geldanamycin belongs to the ansamycin natural product family, whose members are characterized by a macrolactam ring spanning two positions meta to each other on a benzoquinone, phenol or hydroquinone nucleus. Besides geldanamycin, the ansamycins include the macbecins, the herbimycins, the TAN-420s, and reblastatin.

Geldanamycin and its derivatives are the most extensively studied of the ansamycins. Although geldanamycin originally was identified as a result of screening for antibiotic activity, current interest in it derives from its potential as an anticancer agent. It is an inhibitor of heat shock protein-90 (“Hsp90”), a chaperone protein involved in the folding and activation of numerous “client proteins”, including key proteins involved in signal transduction, cell cycle control and transcriptional regulation. The binding of an inhibitor to Hsp90 disrupts its interactions with a client protein, preventing the latter from being folded correctly with consequent loss of function or susceptibility to proteasome-mediated destruction. Among the Hsp90 client proteins are many mutated or overexpressed proteins implicated in cancer, such as mutant p53, Bcr-Abl kinase, Raf-1 kinase, Akt kinase, Npm-Alk kinase, Cdk4, Cdk6, Wee1, HER2/Neu (ErbB2), and HIF-1α. The possibility that multiple oncogenic client proteins can be simultaneously targeted has generated considerable interest in the development of Hsp90 inhibitors as anti-cancer drugs. See, e.g., Xiao et al., Mini-Reviews Med. Chem. 2006, 6 (10), 1137-1143.
Geldanamycin was considered for development as an anti-cancer drug, but its hepatotoxicity and poor bioavailability led to its withdrawal as a clinical candidate. Nevertheless, interest persists in the development of geldanamycin derivatives having Hsp90 inhibitory activity, but with an improved spectrum of pharmaceutical properties. C17 of geldanamycin has been an attractive focal point, chemically speaking, for the synthesis of geldanamycin derivatives because its methoxy group is readily displaced by a nucleophile, providing a convenient synthetic pathway to the 17-substituted-17-demethoxygeldanamycins. Structure-activity relationship (“SAR”) studies have shown that chemically and sterically diverse 17-substituents can be introduced without destroying antitumor activity. See, e.g., Sasaki et al., U.S. Pat. No. 4,261,989 (1981) (hereinafter “Sasaki”); Schnur et al., U.S. Pat. No. 5,932,566 (1999); Schnur et al., J. Med. Chem. 1995, 38 (19), 3806-3812; Schnur et al., J. Med. Chem. 1995, 38 (19), 3813-3820; and Santi et al., U.S. Pat. No. 6,872,715 B2 (2005); the disclosures of which are incorporated by reference. The SAR inferences are supported by the X-ray crystal co-structure of the complex between Hsp90 and a geldanamycin derivative, showing that the 17-substituent juts out from the binding pocket and into the solvent (Jez et al., Chemistry & Biology 2003, 10, 361-368). The best-known 17-substituted geldanamycin derivatives are 17-allylamino-17-demethoxygeldanamycin (also known as 17-AAG or tanespimycin, Sasaki, supra) and 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin (also known as 17-DMAG or alvespimycin, Snader et al., U.S. Pat. No. 6,890,917 B2 (2005)), both of which are currently undergoing clinical trials.

It is desirable to develop additional ansamycin therapeutic agents, based on a structural motif other than 17-methoxy substitution in geldanamycin and having the potential for a more attractive spectrum of properties. One possible motif is represented by ansamycins having a non-benzoquinone aromatic nucleus. As noted above, some such ansamycins are naturally occurring: Macbecin II, the herbimycins, TAN420B, TAN420D, and reblastatin. Some semi-synthetic compounds having this motif also have been reported: Rinehart, Jr., et al., U.S. Pat. No. 3,987,035 (1976); Muroi et al., U.S. Pat. No. 4,421,688 (1983); Schnur, U.S. Pat. No. 5,387,584 (1995); Cullen et al., WO 93/14215 A1 (1993); Sasaki et al., JP 57-163369A (1982); and Yamaguchi et al., WO 2007/001049 A1 (2007); the disclosures of which are incorporated by reference. However, for various reasons non-benzoquinone ansamycins have progressed as drug candidates, with one possible exception as discussed infra.